Quantification of frequency-dependent genetic architectures in 25 UK Biobank traits reveals action of negative selection
Quantification of frequency-dependent genetic architectures in 25 UK Biobank traits reveals action of negative selection
复制标题
DOI：
10.1038/s41467-019-08424-6
复制
发表时间：
2019-02-15
影响因子：
16.6
通讯作者：
Price, Alkes L.
中科院分区：
文献类型：
--
作者：
Schoech, Armin P.;Jordan, Daniel M.;Price, Alkes L.
了解罕见变异的作用对于阐明人类疾病的遗传基础非常重要。负选择可以导致罕见变异比常见变异具有更大的每个等位基因效应大小。在这里，我们开发了一种方法来估计SNP效应大小的次要等位基因频率（MAF）依赖性。我们使用一个模型，其中每个等位基因的效应大小的方差与[p（1- p）]（alpha）成比例，其中p是MAF，alpha的负值意味着罕见变异的效应大小更大。我们估计了25种英国生物库疾病和复杂性状的α。所有性状均产生负α估计值，最佳拟合平均值为-0.38（s.e. 0.02）跨性状。尽管罕见变异效应量较大，但罕见变异（MAF
Understanding the role of rare variants is important in elucidating the genetic basis of human disease. Negative selection can cause rare variants to have larger per-allele effect sizes than common variants. Here, we develop a method to estimate the minor allele frequency (MAF) dependence of SNP effect sizes. We use a model in which per-allele effect sizes have variance proportional to [p(1- p)](alpha), where p is the MAF and negative values of alpha imply larger effect sizes for rare variants. We estimate alpha for 25 UK Biobank diseases and complex traits. All traits produce negative alpha estimates, with best-fit mean of -0.38 (s.e. 0.02) across traits. Despite larger rare variant effect sizes, rare variants (MAF